Our working hypothesis states that there exists a normal intravascular balance between prostacyclin produced by the vessel wall and platelet arachidonic acid metabolites (i.e., thromboxane A2) which could be altered by the presence of a primary tumor or circulating tumor cells and/or their shed membrane vesicles. This hypothesis predicted that arachidonic acid metabolism by the tumor cell, the platelet, and the vessel wall were fundamental determinants in the sum total of the interaction of those cell types. We also proposed that endogenous prostacyclin production may be a natural deterrent to metastasis. That hypothesis elicited two lines of investigation; one which dealt with the role of prostacyclin and related compounds in tumor metastasis, and the second, which focused on the platelet and its role in tumor metastasis. When this study was initiated, platelet thromboxane A2 was considered to be a prime mediator of stimulus-induced platelet aggregation. Therefore, the proposal focused on the role of thromboxanes in tumor cell induced platelet aggregation. We now have evidence that the situation is far more complex than originally envisioned. We still believe that arachidonic acid metabolites are fundamental determinants in the interaction of platelets, tumor cells endothelial cells and their subendothelial matrix. However, we can no longer limit our investigation to prostacyclin and thromboxane A2. We have gained much new knowledge regarding the role of other elcosanoid metabolites produced by tumor cells, platelets, and endothelial cells, and in the role these metabolities play in the interactions of these three cell types. Finally, we have recently demonstrated the presence of glycoproteins on tumor cell which are immunologically related to the platelet glycoproteins lib and llla in addition to other integrin receptors. We have obtained evidence that one of these integrin glycoproteins plays a major role in platelet adhesion to the tumor cell membrane and tumor cell adhesion to endothelial cells, subendothelial matrix, and its components. The lipoxygenase product of arachidonic acid [i.e., 12(S)-HETE] stimulates the surface expression of an integrin receptor and increases tumor cell adhesion to a variety of substrata. This effect demonstrates stereo specificity and geometric specificity. Further, we demonstrate that a lipoxygenase product of linoleic acid (i.e., 13- HODE) antagonizes the effect of 12-HETE. The phorbol ester TPA also enhances tumor cell adhesion by a lipoxygenase dependent is mechanism and is antagonized by 13-HODE. The mechanism by which 12-HETE and 13-HODE regulate tumor cell integrin receptor expression and adhesion, may center on translocation on protein kinase C from the cytoplasmic to membrane bound form as we demonstrate that 12-HETE enhances and 13-HODE inhibits protein kinase C association with tumor cell membranes. Finally, we demonstrate a positive correlation between lung colonization potential tumor cell expression of one integrin receptor and metabolism of arachidonic acid to 12-HETE in the present study, we propose to difinitively identify tumor cell metabolites of arachidonic acid and linoleic acid in murine and human tumor cells, test the effects of these metabolites, and related lipoxygenase metabolites on integrin receptor expression and tumor cell adhesion to a variety of biological substrata. In addition, we propose to determine the effects of these various lipoxygenase products on translocation of protein kinase C. Finally, we will attempt to correlate tumor cell lipoxygenase activity and integrin receptor expression with metastatic potential in vivo.